5-Amino-2-fluoropyridine → (S)-N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide

HRID 1485302Notes

Reaction equation

HRID 1485302 reaction equation
[F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:14]([C:17]1[NH:21][N:20]=[C:19]([NH:22][C:23]2[C:24]3[CH2:40][CH2:39][CH2:38][C:25]=3[N:26]=[C:27]([N:29]3[CH2:33][CH2:32][CH2:31][CH:30]3[C:34](OC)=[O:35])[N:28]=2)[CH:18]=1)([CH3:16])[CH3:15]>C1COCC1>[F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:34]([C@@H:30]2[CH2:31][CH2:32][CH2:33][N:29]2[C:27]2[N:28]=[C:23]([NH:22][C:19]3[CH:18]=[C:17]([CH:14]([CH3:16])[CH3:15])[NH:21][N:20]=3)[C:24]3[CH2:40][CH2:39][CH2:38][C:25]=3[N:26]=2)=[O:35])=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 8194405-Amino-2-fluoropyridineHCID 86723630methyl 1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylateHCID 178418918HCID 178418918, compound

Product 1

HCID 76072890(S)-N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamideYield 37.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

To a solution of 6-fluoropyridin-3-amine (6.05 g, 13 mmol) in dry THF (100 mL) was added 2M solution of isopropylmagnesium chloride in THF (27 mL, 54 mmol) dropwise under nitrogen at 0° C. The resultant mixture was stirred at 0° C. for 20 min. To this solution was added a solution of methyl 1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate (5 g, 13 mmol) in THF (20 mL) dropwise at 0° C. and the reaction mixture was allowed to stir at RT for 2 h. The reaction was quenched with saturated ammonium chloride solution (50 mL). The product was extracted with EtOAc (2×40 mL) and the organic layer was dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave solid residue which was purified by column chromatography on silica gel using 1-2% MeOH-DCM system as eluent followed by chiral purification to afford (S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (2.2 g). 1H NMR (CDCl3, freebase) δ (ppm): 1.22 (d, 6H), 1.90-2.21 (m, 6H), 2.60-2.70 (m, 1H), 2.72 (t, 2H), 2.88 (t, 2H), 2.81-2.96 (m, 1H), 3.60-3.80 (m, 2H), 4.77 (d, 2H), 6.40 (s, 1H), 6.74 (s, 1H), 6.82 (d, 1H), 7.90 (s, 1H), 8.13 (s, 1H). The other enantiomer was prepared using the (R) chiral starting material.

Workup

  1. customThe reaction was quenched with saturated ammonium chloride solution (50 mL)
  2. extractionThe product was extracted with EtOAc (2×40 mL)
  3. dry with materialthe organic layer was dried over anhydrous sodium sulfate
  4. customRemoval of EtOAc under reduced pressure
  5. customgave solid residue which
  6. customwas purified by column chromatography on silica gel using 1-2% MeOH-DCM system as eluent
  7. customfollowed by chiral purification

Sources & evidence

ORD record
ord-4ec7ce54f347417b9e6abadf364ce914
Source dataset
uspto-grants-2016_08
Patent number
US09422267B2

Reaction notes

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